DENDRITIC AND T CELLS IN ANTI-BACTERIAL Ig RESPONSES

树突状细胞和 T 细胞在抗菌 Ig 反应中的作用

• 批准号: 6317430
• 负责人: CLIFFORD M SNAPPER
• 金额: $ 25.94万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6317430
• 关键词: CD40 molecule; MHC class II antigen; Streptococcus pneumoniae; antibacterial antibody; antibody formation; antigen presentation; bacterial antigens; bactericidal immunity; cellular immunity; cytokine; dendritic cells; helper T lymphocyte; laboratory mouse; protein biosynthesis; tissue /cell culture

DESCRIPTION (provided by applicant): Infections due to extracellular bacteria continue to pose a significant global health problem. This is due in large part to the continual emergence of antibiotic-resistant strains. Hence, there exists an urgent need for development of protective vaccines. Immunity is mediated by antibodies to the bacterial polysaccharides (PS) as well as proteins. However, little is known regarding the parameters that mediate in vivo anti-PS and anti-protein responses to intact extracellular bacteria, although such information has relevance to the rational design of immunotherapies for these agents. We have established an in vivo model system for investigating the mechanism of induction of anti-PS and anti-protein Ig isotypes in response to intact Streptococcus pneumoniae. Specifically, the Ig isotype response to the phosphorylcholine (PC) determinant, present on the bacterial cell wall C-PS is studied and compared to the humoral response to a cell wall protein, pneumococcal surface protein A (PspA). We show that induction of optimal anti-PC and anti-PspA responses both require CD4+TCR-a/b+ T cells and B7-dependent costimulation, although memory fails to develop for induction of PC-specific Ig. Of interest, the mechanisms underlying the T cell-dependence of these two responses are distinct. We further show that dendritic cells (DCs) can phagocytose S. pneumoniae upon transfer into naive mice, induce both anti-PC and anti-PspA Ig responses, and the formation of PspA-specific memory. The general aims of this application are to elucidate the mechanisms by which DCs respond to and process an intact extracellular bacterium for induction of both T cell-dependent PC- and PspA-specific Ig isotypes in vivo, and determine the mechanisms underlying the distinct forms of T cell help that stimulate these respective antigen-specific Ig isotype responses. Specifically, we will utilize a number of in vitro and in vivo model systems to determine 1) the parameters that regulate DC activation and antigen presentation in response to R36A, 2) the relative contribution of DC subsets, and 3) the role of DC cytokines and accessory molecules, including CD40, MHC class 11, and Toll-like receptors. In this context, 4) the differential requirements for DC stimulation of T cell help for the anti-PC versus the anti-PspA response will be determined. These data will be the first to establish the detailed parameters that mediate a physiological antigen-specific humoral immune response to an intact extracellular bacterium, including the delineation of the fundamental differences between polysaccharide and protein-specific Ig isotype responses.

描述（由申请人提供）：由于细胞外细菌引起的感染 继续构成重大的全球健康问题。这在很大程度上应 抗生素抗性菌株的持续出现。因此，存在 迫切需要开发保护性疫苗。免疫力是由 细菌多糖（PS）和蛋白质的抗体。然而， 关于介导体内抗PS的参数和 抗蛋白质对完整细胞外细菌的反应，尽管 信息与这些免疫疗法的合理设计有关 代理商。 我们已经建立了一个体内模型系统，用于研究 响应完整的抗PS和抗蛋白质Ig同种型的诱导 肺炎链球菌。具体而言，Ig同种型响应对 细菌细胞壁C-PS上存在的磷酸胆碱（PC）决定因素为 研究并与对细胞壁蛋白的体液反应进行了比较， 肺炎球形表面蛋白A（PSPA）。我们证明了最佳的诱导 抗PC和抗PSPA响应都需要CD4+ TCR-A/B+ T细胞和 尽管记忆并没有发展为诱导的记忆，但依赖于B7 PC特异性IG。有趣的是，T细胞依赖性的基础机制 这两个反应是不同的。我们进一步表明树突状细胞（DC） 转移到幼稚小鼠中时，可以吞噬肺炎链球菌链球菌吗？ 抗PC和抗PSPA Ig响应，以及PSPA特异性内存的形成。 该应用程序的一般目的是阐明 DC响应并处理完整的细胞外细菌，以诱导 T细胞依赖性PC和PSPA特异性Ig同型在体内，并确定 刺激T细胞的不同形式的基础机制 这些各自的抗原特异性Ig同种型反应。具体来说，我们会的 利用许多体外和体内模型系统来确定1） 调节直流激活和抗原表现的参数响应 R36A，2）DC子集的相对贡献，3）DC的作用 细胞因子和辅助分子，包括CD40，MHC类别11和Toll样分子 受体。在这种情况下，4）直流刺激的差异要求 抗PC与抗PSPA响应的T细胞帮助将是 决定。 这些数据将是第一个建立中介参数的数据 生理抗原特异性的体液免疫反应 细胞外细菌，包括基本的描述 多糖和蛋白质特异性Ig同种型反应之间的差异。